High Diastereoselectivity Research Articles

Catalytic, dearomative 2,3-difluorination of indoles

Indolines, characterized by their diverse biological activities and structural significance, have garnered considerable attention in the realms of natural product synthesis and drug discovery. Concurrently, the incorporation of fluorine atoms into organic molecules has emerged as a powerful strategy to enhance their pharmacological properties. Herein, we report a robust and diastereoselective approach for the synthesis of 2,3-difluorinated indolines through the iodine(I/III)-catalyzed dearomatization of readily available indoles. The protocol operates under mild conditions, displaying excellent functional group tolerance and remarkable diastereoselectivity. By employing this developed protocol, vicinal-difluorinated analogues of indole-containing drugs can be efficiently accessed. Theoretical calculations have shed light on the underlying reaction mechanism, proposing the formation of a β-fluorine-substituted carbocation intermediate. It is postulated that the observed high diastereoselectivity can be attributed to the dipole-dipole interactions facilitated by the C–F bond. Crystallographic analysis has revealed the profound impact of fluorine atom introduction on the conformational preferences of the indoline core. Given the unique structural characteristics and pharmacological significance of 2,3-difluorinated indolines, we anticipate their widespread application in medicinal chemistry and drug discovery endeavors.

Synthesis of 10-Membered Azecines through Pd-Catalyzed Formal [6+4] Cycloaddition and Their Transannular Reaction to Polycyclic Compounds.

Azecine fragments are frequently presented in natural products and bioactive compounds. However, minor efforts have been devoted to these 10-membered N-heterocycles, and their synthesis is still challenging. Reported herein is the first catalytic formal [6+4] cycloaddition for the synthesis of 10-membered azecines. Under palladium catalysis, the reaction of δ-vinylvalerolactones and benzofuran-derived azadienes proceeds smoothly to afford benzofuran-fused azecines with high diastereoselectivity in moderate to good yields. A unique transannular reaction of these 10-membered azecines for the construction of polycyclic compounds is also demonstrated.

Diastereoselective Pd-catalyzed Decarboxylative (4 + 2) Cycloaddition Reactions of 4-Vinylbenzoxazinanones and 2-Nitro-1,3-enynes.

A formal palladium-catalyzed decarboxylative (4 + 2) cycloaddition reaction between 4-vinylbenzoxazinanones and 2-nitro-1,3-enynes has been developed to produce highly valuable, densely functionalized tetrahydroquinolines in moderate to excellent yields with high diastereoselectivity under mild reaction conditions. The optimised protocol tolerates a range of substituted 2-nitro-1,3-enynes, which represent an under-utilized class of dipolarophile for transition-metal catalyzed cycloadditions. The employed reaction methodology facilitates efficient cycloaddition with both N-H- and N-Ts-4-vinylbenzoxazinanone dipole precursors. The stereochemistry of the major and minor diastereomeric (4 + 2) cycloadducts was determined by single crystal X-ray analyses. A mechanistic rationale for the high intrinsic diastereoselectivity and preliminary enantioselective experiments are also presented. The tetrahydroquinoline cycloadduct products feature numerous pendant functionalities, including a vinyl handle, an internal alkyne motif and a nitro functionality (which functions as a latent C-3 nitrogen substituent) for further synthetic manipulations.

NHC-Catalyzed Enantioselective Synthesis of Tetracyclic δ-Lactones by (4 + 2) Annulation of ortho-Quinodimethanes with Activated Ketones.

The N-heterocyclic carbene (NHC)-catalyzed generation of ortho-quinodimethanes (o-QDMs) from 9H-fluorene-1-carbaldehydes followed by the interception with activated ketones resulting in the enantioselective synthesis of tetracyclic δ-lactones is presented. High diastereoselectivity of products, remote C(sp3)-H functionalization, broad substrate scope, and mild reaction conditions are the notable features of the present (4 + 2) annulation.

Palladium-Catalyzed Modular Assembly of P-Stereogenic and Axially Chiral Phosphinooxazoles (PHOX) Ligands by C-P Bond Cleavage/Intermolecular C(sp2)-H Bond Functionalization.

Chiral P,N-ligands are of great interest and importance in the fields of metal-catalyzed enantioselective transformations and have found numerous applications spanning drug and polymer synthesis. Here, modular assembly of diverse P-stereogenic and axially chiral phosphinooxazoles ligands is achieved through palladium-catalyzed asymmetric cleavage of C-P bond/intermolecular C-H bond functionalization in high atroposelectivities and diastereoselectivities of up to >99% ee and >25:1 dr. This protocol features broad substrate scope and provides an avenue for facile construction of new P-stereogenic and axially chiral phosphinooxazoles ligands directly from the phosphonium salts and benzoxazoles/benzothiazoles. Evaluation of the synthesized P-stereogenic and axially chiral phosphinooxazoles ligands in two model catalytic asymmetric reactions illustrates the potential of our strategy to access valuable chiral molecules.

Diastereoselective construction of carbazole‐based spiropyrrolidines and spiropyrrolizidines via cycloaddition reaction

AbstractA series of new spiro heterocyclic compounds having carbazole and pyrrolidine units were successfully synthesized through a one‐pot, three component, 1,3‐dipolar cycloaddition reaction in good yields with high diastereoselectivity. Simple reaction, easily accessible chemicals, high yield and diastereoselective formation of monospiropyrrolidine and monospiropyrrolizidine carbazole derivatives in one step are some advantages of this method. The structure of the obtained products was characterized by using spectroscopic techniques.

Enantioselective Synthesis of 2,3,3a,8a-Tetrahydrofuro[2,3-b]benzofuran Scaffolds Enabled by Cu(II)/SPDO-Catalyzed [3+2] Cycloaddition of 2,3-Dihydrofuran and Quinone Esters.

An asymmetric [3+2] cycloaddition of quinone esters with 2,3-dihydrofuran has been realized via a newly developed Cu(II)/SPDO complex. It provides straightforward access to 2,3,3a,8a-tetrahydrofuro[2,3-b]benzofurans (TFB) with high enantioselectivity (up to 97.5:2.5 er) and diastereoselectivity (all >20:1 dr). The resulting adducts contain two adjacent stereocenters and a continuously functionalized benzene ring. Additionally, this transformation could be easily performed on a gram scale, allowing for expedient synthesis of natural dihydroaflatoxin D2 and aflatoxin B2.

An Efficient Synthesis of Spirocyclopropanes by [2+1] Annulation of α,β‐Unsaturated Carbonyl Compounds with Nitroacetates

AbstractAn efficient synthesis of spirocyclopropanes was developed via [2+1] annulation of α,β‐unsaturated carbonyl compounds with nitroacetates. This protocol features advantages such as simple operation, broad substrate scope, high diastereoselectivity and good to excellent yields. Moreover, this work represents the first example of assembling spirocyclopropane derivatives from nitroacetates.

Divergent Photosensitizer Controlled Reactions of 4‐Hydroxycoumarins and Unactivated Olefins: Hydroarylation and Subsequent [2+2] Cycloaddition

AbstractHerein, we report a photoinduced approach for hydroarylation of unactivated olefins using 4‐hydroxycoumarins as the arylating reagent. Key to the success of this reaction is the conversion of nucleophilic 4‐hydroxycoumarins into electrophilic carbon radicals via photocatalytic arene oxidation, which not only circumvents the polarity‐mismatch issue encountered under ionic conditions but also accommodates a broad substrate scope and inhibits side reactions that were previously observed. Moreover, divergent reactivity was achieved by changing the photocatalyst, enabling a subsequent [2+2] cycloaddition to deliver cyclobutane‐fused pentacyclic products that are otherwise challenging to access in high yields and with high diastereoselectivity. Mechanistic studies have elucidated the mechanism of the reactions and the origin of the divergent reactivity.

Divergent Photosensitizer Controlled Reactions of 4-Hydroxycoumarins and Unactivated Olefins: Hydroarylation and Subsequent [2 + 2] Cycloaddition.

Herein, we report a photoinduced approach for hydroarylation of unactivated olefins using 4-hydroxycoumarins as the arylating reagent. Key to the success of this reaction is the conversion of nucleophilic 4-hydroxycoumarins into electrophilic carbon radicals via photocatalytic arene oxidation, which not only circumvents the polarity-mismatch issue encountered under ionic conditions but also accommodates a broad substrate scope and inhibits side reactions that were previously observed. Moreover, divergent reactivity was achieved by changing the photocatalyst, enabling a subsequent [2+2] cycloaddition to deliver cyclobutane-fused pentacyclic products that are otherwise challenging to access in high yields and with high diastereoselectivity. Mechanistic studies have elucidated the mechanism of the reactions and the origin of the divergent reactivity.

Asymmetric Hydrogenation of Tetrapyridine‐Type N‐Heteroarenes Using Phosphine‐Free Ruthenium Diamine Catalysts†

Comprehensive SummaryChiral ruthenium‐catalyzed enantioselective hydrogenation of tetrapyridine‐type N‐heteroarenes was firstly developed. The partial reduction of adjacent tetraheteroaromatic substrates proceeded smoothly in the presence of phosphine‐free chiral cationic ruthenium diamine complexes, affording unprecedented high reactivity, enantioselecitivity and diastereoselectivity (up to 93% yield, >99% ee and 92 : 8 dr). The potential application of chiral tetradentate pyridine‐amine products as chiral ligands has been demonstrated in the Cu‐catalyzed asymmetric Friedel–Crafts alkylation reaction between indoles and nitroalkenes.

Palladium‐Catalyzed [4+2] Cycloaddition of Vinyl Benzoxazinanones with 1,3‐Indanedione: Approach to Spiro‐Tetrahydroquinoline Scaffolds

AbstractA palladium catalyzed decarboxylative [4+2] cycloaddition of vinyl benzoxazinanones with 2‐arylidene indan‐1,3‐dione has been established, which afford a series of bioactive spiro‐tetrahydroquinolines (27 examples) in moderate to good yield (up to 87 %) with high diastereoselectivities. The synthetic utility of this reaction was demonstrated by gram‐scale synthesis. Compounds synthesized by this method potently inhibited proliferation in a panel of cancer cell lines. Particularly, the most potent compounds 3 ae, 3 ah, 3 aj and 3 fa displayed selective inhibition of MDA‐MB‐231 breast carcinoma cells with IC50 values of 1.292, 0.6118, 0.6558, 1.656 and 2.215 μM, respectively.

Development of a Continuous Flow Baldwin Rearrangement Process and Its Comparison to Traditional Batch Mode.

A new and highly efficient continuous flow process is presented for the synthesis of aziridines via the thermal Baldwin rearrangement. The process was initially explored using traditional batch synthesis techniques but suffered from moderate yields, long reaction times, and moderate diastereoselectivities. Here we demonstrate that the process can be greatly improved upon its transfer to continuous flow, which afforded the aziridine targets in high yields, short reaction times, and consistently high diastereoselectivities, with the high-throughput process rendering multigram quantities of product in short periods of time. In addition, flow processing extended the substrate scope including several examples that had failed in batch mode, thus demonstrating the value of this overlooked entry into valuable aziridine species.

Anion Cascade Reactions II: Synthesis of 3-Isoquinuclidone-Based Bridged Polycyclic Lactams.

A facile and convenient anion cascade strategy was developed for the synthesis of bridged-ring amides in moderate to excellent yields in one step in the presence of tBuOK in EtOH under mild conditions, starting from various cheap and commercially available 2-cyanoacetamides and precisely designed straight-chain and annular 1,4-dienones. This simple protocol was generally applicable to a wide range of substrates with high chemical conversion and diastereoselectivity.

Diastereoselective Construction of Fused Carbocyclic Pyrrolidines via a Copper-Catalyzed [3 + 2] Cycloaddition: Total Syntheses of Pancratinines B-C.

A Cu-catalyzed diastereoselective [3 + 2] cycloaddition of 2-arylaziridines and cyclic silyl dienol ethers was developed to efficiently construct fused-[5,n] carbocyclic pyrrolidines, which are widespread in bioactive natural products. Mechanistic studies revealed that the high diastereoselectivity of this transformation arose from a sequential retro aza-Michael/epimerization/aza-Michael process. Taking advantage of this newly developed method, the first total syntheses of pancratinines B and C were concisely realized.

Organocatalytic Synthesis of Furan-Embedded Styrene Atropisomers.

Herein, we report the first synthesis of furan-embedded styrene atropisomers via the reaction between 1-(aryl-ethynyl)-naphthalen-2-ol and γ-hydroxyenone. The reaction proceeds through in situ furan formation from γ-hydroxyenone. The styrene derivatives were obtained in moderate to good yields with high diastereoselectivities with a catalytic amount of PTSA. Few applications such as triazole formation and cross-coupling reactions have been demonstrated. A preliminary catalytic asymmetric version was also reported.

A Scope of Chiral Cyclopropanations of Various α-functionalized Diazoketone Derivatives with Styrene Catalyzed by p-Nitro Ru(II)-diphenyl- Pheox Complex

Abstract: Following the success of the first intermolecular cyclopropanations of diazo acetoxy acetone with olefins using a novel p-nitro-Ru(II)-diphenyl-Pheox catalyst, other α-functionalized diazoketones have synthesized using the same reaction conditions. Consequently, chiral cyclopropyl products were formed with excellent yield (up to 87% yield), high diastereoselectivity (up to 99:1), and high enantioselectivity (up to 90% ee).

Solvent Directed Diastereodivergent Synthesis of Spiro‐Oxindoles with Quaternary Carbon Center Forming

AbstractAn efficient method has been developed for the solvent‐directed diastereodivergent cyclization reactions with quaternary center formation. Various spiro‐oxindole diastereoisomers were synthesized with good yields (up to >99 %) and moderate to high diastereoselectivities (up to >20 : 1). Further study on NMR studies indicates that the key to this approach lies in different interactions between the substrate and organocatalyst across diverse solvents. This methodology may have significant implications for switchable, solvent‐directed diastereodivergent synthesis.

Selective construction of dispiro[indoline-3,2'-quinoline-3',3''-indoline] and dispiro[indoline-3,2'-pyrrole-3',3''-indoline] via three-component reaction.

A convenient synthetic procedure for the construction of novel dispirooxindole motifs was successfully developed by base-promoted three-component reaction of ammonium acetate, isatins and in situ-generated 3-isatyl-1,4-dicarbonyl compounds. The piperidine-promoted three-component reaction of ammonium acetate, isatins and the in situ-generated dimedone adducts of 3-ethoxycarbonylmethyleneoxindoles afforded mutlifunctionalized dispiro[indoline-3,2'-quinoline-3',3''-indoline] derivatives in good yields and with high diastereoselectivity. On the other hand, a similar reaction of the dimedone adducts of 3-phenacylideneoxindoles afforded unique dispiro[indoline-3,2'-pyrrole-3',3''-indoline] derivatives with a cyclohexanedione substituent. A plausible reaction mechanism is proposed to explain the formation of the different spirooxindoles.

Investigation of the molecular mechanism and diastereoselectivity in the [3 + 2] cycloaddition reaction between acetonitrile oxide and Cis-3,4-Dichlorocyclobutene: Insights from MEDT and docking study

[3 + 2] cycloaddition (32CA) reactions involving acetonitrile oxide 1 and cis-3,4-dichlorocyclobutene 2 has been investigated via Molecular Electron Density Theory (MEDT) at B3LYP and M06-2X associated with the basis 6–311++G(d,p). The calculated energy profile demonstrates clearly that this reaction is considerably high diastereoselectivity, which is perfectly in accordance with the results of the experiments. The cycloaddition reaction's molecular mechanism has been examined in bonding evolution theory (BET) terms that displays several changes in electron densities along the reaction pathway and demonstrates a one-step process with highly asynchronous transition states. The acetonitrile oxide under study was classified as zwitter-ionic species from the topological analysis of the electron localization function (ELF). In addition, the optimum solvent for performing this cycloaddition is cyclohexane, which is followed by ether and then chloroform. In a further step, a docking survey was carried out for cycloadducts 3, 3-F, 4 and 4-F docked to the main protease of SARS-CoV2 (6LU7) in comparison with ribavirin, revealing that these cycloadducts have lower binding energies than ribavirin.